2 (benzofuranyl amino)-and 2 (thianaphthenyl amino) oxazolines



2(BENZOFURANYL AMI\l)- AND 2(THIANAPH- THEN YL AMINO) OXAZOLINES BarryM. Bloom, Jackson Heights, N. Y., assignor to Chas. Pfizer & Co.,Brooklyn, N..Y., a corporation of Delaware N0 Drawing. Application July8, 1957 Serial No. 670,372

6 Claims. (Cl. 260307) This application is concerned with new and usefultherapeutic agents. In particular, it is concerned with compounds whichare eifective regulators of the central nervous system being especiallyuseful as tranquilizing agents.

The compounds of this invention are substituted and unsubstitutedZ-(benzofuranylamino)-oxazolines, Z-(thianaphthenylamino)-oxazolines,the pharmaceutically acceptable acid addition salts of'these, and withN-(benzofuranyl)-N'-(;8-substituted ethyl)-ureas as well as N(thianaphthenyl)-N-(;8-substituted ethyl)-ureas. The latter compoundsare not only intermediates for the preparation of oxazolines, but arealso useful themselves as regulators of the central nervous system.

Unsubstituted 2-(2-benzofuranylamino)-oxazoline, 2-(2-thianaphthenylamino) -oxazoline, N-(2-benzofuranyl)- N- (fibromoethyl-urea and N- Z-thianaphthenyl -N'- (fi-bromoethyD-urea, compoundswithinthe purview of the instant invention, are represented by the formulas:

isocyanate group. Alternatively, the products may be.

prepared by the reaction between a benzofuranyl isocyanate or a thianaphthenyl isocyanate and an ethylamine with similar substituents in aposition ,8 to the amine group. Thus it is possible to prepareN-(3-benzofuranyl)-N'-;8-chloroethyl urea by the reaction between.

3-aminobenzofuran and fi-chloroethyl isocyanate orbenzofuran-3-isocyanate andfl-chloroethylamine. In either case, theoxazolines of this invention are obtained by the from thefl-chloroethyll urea. The preparation of this compound by each method.

elimination of hydrogen chloride is, shown below.

+ clomcmNoo ll lCONHOHaCHzCI H neomromornol A I] H -no| o In thereaction shown above, the ti-substituted alkylamine and p-substitutedisocyanate are chloroethyl com- Jv NCO I IIVC QNHCHzCHzC pounds and theoxazoline prepared is unsubstituted on therefore, also intended toinclude both of'the methylene groups choice of the proper amine orisocyanate it is possible to prepare oxazolines with one or both of themethylene groups either monosubstituted or disubstituted. It is, withinthe purview of this invention oxazolines in which either or both of themethylene groups are substituted with at least one alkyl groupcontaining up to four carbon atoms, thetotal number of carbon atoms inthese substituents being from one of the oxazoline ring. 'By

' to eight." As an exampleof the preparation of this typeamino-oxazoline to form an acid addition salt.

' and thioalkyl groups each' containing of compound,2-'(4-thianaphthenylamino)-4-ethyl-oxazoline :can beprepared by reacting4-thianaphthenylamine-with fi-bromobutyl isocyanate and subsequentlyheating.

For the preparation of the active urea compounds of this invention, thechlorine of the above equations may be replaced with other halogens suchas bromine or iodine, or with alkyl or aryl sulfonyl groups such asptoluenesulfonyloxy or methanesulfonyloxy. In these cases, the activeoxazoline is formed by the elimination of hydrogen bromide, hydrogeniodide, p-toluenesulfonic acid and methanesulfonic acid respectively.Since the amino-oxazolines are basic in nature, the acid which has beeneliminated from the urea compounds adds to the The free. base may beliberated from the acid addition salt using an alkaline reagent such asammonium hydroxide, sodium hydroxide, sodium bicarbonate, calcium oxideand other obvious equiValeniS- Hydrogen atoms of the benzofuranyl orthianaphthenyl groups in the above reactions may be replaced withcertain substituents to reduce or enhance the therapeutic effect of theunsubstituted compounds. These substituents include from one to threealkyl groups, alkoxy groups up to four carbon atoms, as well as from oneto three chlorine, bromine or iodine atoms. V

The on and 3 carbon atoms of the ethyl portion of the ureas of thisinvention can also .contain substituents which maybe alkyl groupscontaining from one to four carbon atoms, the total number ofsubstituent carbon atoms being from one to eight. The compound whichwill give 2-(S-thianaphthenylamino)-4,4,5,5-tetraethyl oxazoline is N (5thianaphthenyl) N (a,a,p,/3 tetraethyl 3 halo)-ethyl urea. SimilarlyN-(7-benzofuranyl)-N'-( x,udibutyl-fi-halo)-ethylurea andN-(6-benzofuranyl)-N'- (a,B-dibutyl-B-halo)-ethyl urea will yieldrespectively 2 (lbeuzofuranylamino)-4,4-dibutyl oxazoline and 2-(6-heuzoturanylamino)-4,5-dibutyl oxazoline.

ureas of this invention. Analogous Z-thianaphthenyl ureas as well asureas in which the nitrogen is substituted at other than the 2-positionin the benzofuran and thianaphthelene nuclei as well as thecorresponding oxazolines are active and included within the scope oi thepresent invention but are not named for the sake of brevity.

N-(Z-benzofuranyl)-N'- 8-chloroethyl urea N (3 chloro 2 benzofuranyl) NB (p toluenesulfonyloxy)-ethyl ureaN-(3,4-diiodo-2-benzofuranyl)-N'-,8-iodoethyl urea N (4,5 dibromo 2benzofuranyl N (a butyl- ,S-methanesulfonyloxy) -ethyl urea N (3,4,5trichloro 2 benzofuranyl) N (a n propyl-fi-chloro)-ethyl urea N(3-ethyl-9-benzofuranyl -N'-l9-bromoetl1yl ureaN-(Z-benzofuranyl)-N'-(a,u-dimethyl-)fi-bromoethyl urea N( 5,6-diethyl-2-benzofuranyl) -N-;8-iodoethyl urea N (3 n butoxy 2benzofuranyl) N ,8 methanesulfonyloxy ethyl urea N (4,7 dimethoxy 2'benzofuranyl) N (a,

methyl-fi-p-toluenesulfonyloxy)-ethyl urea N (5,6 dithiopropyl 2benzofuranyl) N l3 bromoethyl urea N (3 thioethyl 2 benzofuranyl) Np-butyl-B-iodo) -ethyl ureaN-(4,S-diethoxy-Z-benzofuranyl)-N'-fi-chloroethyl urea The amines andisocyanates necessary for the preparation of the compounds of thisinvention are known or can be prepared by procedures known in the art.The ethyl isocyanates, for example, are prepared by treatment of thecorresponding acid chlorides with. sodium. azide. The ethylamines can beprepared by the Hofinann reaction employing the corresponding amides..Benzofuransare generally prepared by ring closure of phenols and phenolethers, by the cyclization of. O-carbalkoxymethoxy benzaldehydes or bythe condensation of a sodium phenoxide with the appropriatelysubstituted alkyl haloacetoacetate. These methods are discussed in, forex ample, Gilmans Organic Chemistry by Wiley, R. 1-1., vol. IV, page741, John Wiley & Sons, Inc., 1953. Thianaphthenes are prepared by thecyclization of O-mercaptow-chlorostyrenes or by oxidative cyclization ofO-mer capto-cinnamic acid. These procedures are described by Steinkopfin Die Chemie des T hiophens," Theodor Steinkopf, Dresden, 1941. Thevarious substituted compounds are prepared by conventional meansinvolving either direct substitution on the benzofuran and thianaphthenenuclei or substitution prior to cyclization.

In carrying out the reaction for the preparation of the valuablecompounds of the instant invention, the amine and isocyanate arecontacted in benzene or an equivalent aromatic solvent. Hydrocarbonsolvents, both aromatic and aliphatic can be used. Halogenated andnitrated hydrocarbon solvents are also useful. There may be mentioned byway of example, chloroform, carbon tetrachloride, ethylene chloride,ethylene dichloride, chlorobenzene, toluene, xylene, nitrobenzene andnitrotoluene. Lower oxygenated aliphatic solvents, particularly otherscontaining up to eight carbon atoms, are particularly useful. r 1

The reaction between an amine and an isocyante generally takes placewithout the application of heat. In fact with some of the more reactivecompounds, it is best to carry out the reaction in an ice bath. However,as in other reactions of this type, the progress of the reaction (amethyl may be hastened by the use of heat. It has been found I thattemperatures from 0 to ll0 C. .are useful and that most of the aminesand isocyanates react to form" products of this invention below 50 C.

Formation of an oxazoline acid addition salt by the elimination of anacid from the urea compound is best carried out in refluxing aqueoussolution although lower alkanols such as methanol, ethanol, propanol, orbutanol may be used.

Although both reactions of the synthesis proceed readily at atmosphericpressure, for certain applications it may be desirable to use increasedpressure. Pressures as high as 100 atmospheres may be useful.

The compounds of this invention are useful as central nervous; systemdepressants and when administered to rodents, it is found-that theysignificantly reduce the spon taneous motility of these animals. Similarresults are observed with monkeys and other higher animals.

Each of the types of compounds of this invention has its own specificadvantage. For example, although both the ureas and the oxazolines areeffective therapeutically, the oxazolines produce their eifect in ashorter time. On the other hand, the ureas, while they require asomewhat longer time to take their effect, are less toxic and can,therefore, be administered in larger dosages. This suggests that undercertain circumstances it may be advantageous to administer both agentssimultaneously to produce both a rapid and a prolonged therapeuticaction.

The ureas are neutral and do not form the acid addition salts. Theoxazolines, however, are weakly basic and do form acid addition salts.These salts because of their water solubility, are more readilyutilizable for the preparation of aqueous parenteral solutions than arethe free bases.

With reference to the oxazolines of this invention, it is specificallyintended to include within the purview of the invention the acidaddition salts which these compounds form with acids havingpharmaceutically acceptable anionsf The term, pharmaceuticallyacceptable anion has a definite meaning to one skilled in the art. It isdefined as a non-toxic anion of any of the simple acids commerciallyused therapeutically to neutralize basic medicinal agents when the salt.thereof is to be administered to a human host. These acids include, forexample, hydrochloric, hydrobromic, hydroiodic, sulfuric, succinic,maleic, tartaric, citric, glycolic and others. The pharmaceuticalactivity of the molecule is primarily a function of the cation, theanion serving chiefly to supply electric neutrality.

By reference to the reaction described above, it can be seen that in theordinary practice of the process of the invention, the oxazolinesproduced will be hydrobromides, hydrochloridcs, hydriodides,methanesulfonic acids or p-toluenesulfonic acids. These acids can beconverted to other pharmaceutically acceptacle acids by procedures wellknown to those skilled in the art. One high useful method comprisescontacting the acid addition salt with a basic anion exchange resin, forexample, a highly basic compound such as the one available from Rohm 8:Haas Company under the name Amberlite IRA400". This resin is apolyquaternary ammonium compound which is prepared by chlorornethylatinga highly cross-linked copolymer of styrene and divinylbenzene followedby treatment of the chloromethylated material with a tertiary amine suchas trimethylamine. To prepare an acid addition salt of this invention,for example, the citrate, the resin is first contacted with an aqueoussolution of citric acid whereupon an anion exchange takes placeconverting the quaternary halide to the citrate. The citrate resin isthen contacted with an acid addition salt prepared as described aboveand a further anion exchange takes place.

converting the acid addition salt to the citrate and leav mg the anionof the original salt on the resin. The citrate resin can be recoveredfrom the eluate by a number of.

methods such as evaporation or solvent precipitation.

This same procedure can be used to prepare nitrates, sulfates, acetates,and other acid addition salts.

, The agents of this invention may be administered alone but aregenerally administered with a pharmaceutical carrier selected on thebasis of the chosen route of administration and standard pharmaceuticalpractice. For example, they may be administered orally in the form of 5.tablets or capsules containing such excipients as starch, milk sugar,certain types of clay, etc. They may be administered orally in the formof elixirs or oral suspensions which may contain coloring and flavoringagents. They may be injected parenterally and for this use may beprepared in the form of sterile aqueous solutions containing othersolutes such as saline or glucose in suflicient quantityto make thesolution isotonic. For intramuscular administration compositions of thecompounds of this invention may be prepared in an oil base such aspeanut or sesame oil.

The compounds of this invention are central nervous system regulatorsand are useful in the same manner as other regulators of the centralnervous system. The dosage is generally of the same order of magnitudeas the dosage required with other therapeutic agents of this e. incertain instances it may be found that because of their high order ofactivity the optimum dosage of the compounds of this invention will belower than the optimum dosage of other compounds generally recommendedfor the same use. In general, the physician or veterinarian willdetermine the dosage which will be most suitable for a particularapplication, and as might be expected, it will vary with the particulardrug chosen and with the desired effect. It will vary with the age,weight and general health of the patient under treatment and withvarious other factors which will be determined by the physician orveterinarian in attendance. When the drugs are administered orally alarger quantity will be required to produce the same efiiect as asmaller quantity given parenterally. It has been found that parenteraladministration of from 0.5 mg. to 250 mg. of active agent generallygives the desired effect.

The compositions of this invention may take a variety of forms.percentage of active ingredients may be varied. It is necessary that anactive ingredient form a proportion of the composition such that asuitable dosage form will be obtained. Obviously compositions with lessthan 0.005% by weight of active ingredient are suitable, it is preferredto use compositions containing not less than 0.005% of the active agentbecause otherwise the amount of carrier becomes excessively large.Activity increases with the concentration of the active agent. Thepercentage by weight of active agent may be 10, 50, 75, 95% or evenhigher. Dosage unit forms may be prepared with a minor proportion of acarrier and a major proportion of active materials and vice-versa.

The following examples are given solely for the purpose of illustrationand are not to. be construed as limitations of this invention, manyvariations of which are possible without departing from the spirit orscope thereof.

EXAMPLE I N-(Z-benzofurnnyl) -N'-p-chloraethyl urea A solution of icecold 50% (150 g.) is shaken with a suspension ethylamine hydrochloridein 420 ml. of benzene. The benzene" layer containing the free base isseparated and dried over a small amount of potassium hydroxide. Thedrying .agentis removed by filtration. To this solution an equimolarbenzene solution of Z-benzofuranyl isocyanate is added dropwise withcooling. The solution is allowed to stand for one hour during which timethe product separates and is recovered by filtration.

The same procedure was used to prepare N-(3-benzofuranyl)-N/8-chloroethyl urea using equimolar amounts of ,B-chloroethylaminehydrochloride and 3-benzofuranyl isocyanate.

potassium hydroxide of 133 g. of fl-chloroligag-l z s iq F ld 0 po m hyroxide Various diluents may be employed and the g.) is shaken with asuspension of 133 g. of p-i0doethylamine hydrochloride in 420 ml. ofbenzene. The benzene layer containing the free base is separated anddried over a small amount of potassium hydroxide. The

N- (Z-benzofuranyl) -N'- 3-bromoethyl urea A solution of ice cold 50%potassium hydroxide (150 g.) is shaken with a suspension of 133 g. of 3-bromoethylamine hydrochloride in 420 ml. of benzene. The benzene layercontaining the free base is separated and dried over a small amount ofpotassium hydroxide. The drying agent is removed by filtration. To thissolution an equimolar benzene solution of 2-benzo-furanyl isocyanate isadded dropwise with cooling. The solution is allowed to stand for onehour during which time the product separates and is recovered byfiltration.

The same procedure was used to prepareN-(3-benzofuranyl)-N-,6-bromoethyl urea using equimolar amounts offl-bromoethylamine hydrochloride and 3-benzofuranyl isocyanate.

EXAMPLE IV Z-(Z-benzofuranylamino -oxaz0line One liter of water isbrought to boiling and 15 g. of N-(2-benzofuranyl)-N'-B-bromoethyl ureais added. At the end of fifteen minutes reflux time all except a verysmall amount of material dissolves. The flask is cooled in an icebathand the small amount of insoluble material, along with an additionalquantity of material which separates. on cooling, is removed byfiltration. A 14% solution of ammonium hydroxide (30 ml.) is addedslowly and a precipitate forms. The precipitate is extracted with three250 ml. portions of chloroform and the combined extracts washed withwater. The organic layer is dried over anhydrous sodium sulfate andconcentrated in vacuo. The crystalline residue which forms is trituratedwith ether and dried.

The compound 2-( 3 benzofuranylamino) oxazoline was similarly preparedfrom N-(3-benzofuranyl)-N'-/3- bromoethyl urea. I

EXAMPLE V A solution of ice cold 50% potassium hydroxide (150 g.) isshaken with a suspension of 133 g. of ,8-

naphthenyl) N B chloroethyl urea using equimolar amounts offi-chloroethylamine hydrochloride and S-thianaphthenyl isocyanate.

EXAMPLE VI N- (Z-thianaphthenyl)-N-;3-iod0ethyl urea A solution of icecold 50% potassium hydroxide (150 g.) is shaken with a suspension of 133g, of B-iodoethylamine hydrochloride in 420 ml. of benzene. The benzenelayer containing the free base is separated and dried over a smallamount of potassium hydroxide. The

aerated A solution of ice cold 50% potassium hydroxide (150 g.) isshaken with a suspension of 133 g. of [3- bromoethylamine hydrochloridein 420 ml. of benzene. The benzene layer containing the free base isseparated and dried over a small amount of potassium hydroxide. Thedrying agent is removed by filtration. To this solution an equimolarbenzene solution of Z-thianaphthenyl isocyanate is added dropwise withcooling. The solution is allowed to stand for one hour during which timethe product separates and is recovered by filtration.

The same procedure was used to prepare N-(3-thianaphthenyl) N Bbromoethyl urea using equimolar amounts of B-bromoethylaminehydrochloride and 3-thianaphthenyl isocyanate.

EXAMPLE VIII 2- (Z-thianaphzhenylamino) -xaz0line One liter of water isbrought to boiling and 15 g. of N-(Z-thianaphthenyl) N--bromoethyl ureais added. At the end of fifteen minutes reflux time all except a verysmall amount of material dissolves. The flask is cooled in an ice bathand the small amount of insoluble material, along with an additionalquantity of material which separates on cooling, is removed byfiltration. A 14% solution of ammonium hydroxide (30 ml.) is addedslowly and a precipitate forms. tracted with three 250 ml. portions ofchloroform and the combined extracts washed with water. The organiclayer is dried over anhydrous sodium sulfate and concentrated in vacuo.The crystalline residue which forms is triturated with ether and dried.

The compound 2-(3-thianaphthenylamino) -oxazoline was similarly preparedfrom N-(3-thianaphthenyl)-N'-flbromoethyl urea.

' EXAMPLE IX EXAMPLE X 2-(3,4-dimethyl-5-benzofuranylamino)-5-ethyloxazoline One liter ofwater is brought to boiling and g. ofN-(3,4-dimethyl-5-benzofuranyl)-\l'-fichlorobutyl urea is added. At theend or" fifteen minutes reflux time all except a very small amount ofmaterial dissolves. The flask is cooled in an ice bath and the smallamount of insoluble material, along with an additional quantity ofmaterial which separates on cooling, is removed by filtration; A 14%solution of ammonium hydroxide ml.) is added slowly and a precipitateforms. The

precipitate is extracted with three 250 ml. portions of chloroform andthe combined. extracts washed with water.

The organic layer. is driedv over anhydrous sodium sulfate- Theprecipitate is err-- over a small amount of potassium hydroxide.

and concentrated in vacuo. The crystalline residue which forms istriturated with ether and dried.

The compound 2-(3,4-dimethyl-2-benzofuranylamino oxazoline' wassimilarly prepared from N-(3,4-dimethyl- Z-benzofuranyl)-N'-B-bromoethylurea.

EXAMPLE XI N-(2,3-dithi0butyl-4-thianaphthenyl) -N-)8- chlorohexyl ureaA solution of ice cold 50% potassium hydroxide (150 g.) is shaken with asuspension-of g. of fi-chlorohexylamine hydrochloride in 450 ml. ofbenzene. The benzene layer containing the free base is separated anddried The drying agent is removed. by filtration. To this solution anequimolar benzene solution of 2,3-dithiobutyl-4-thianaphthenylisocyanate is added dropwise with cooling. The solution is allowed tostand for one hour during: which time the product separates and isrecovered by filtration.

EXAMPLE XII 2-(2,3-dithi0butyI-4-thianaphthenylamino)- 5-butyl-oxazolineOne liter of water is brought to boiling and 15 g. of N (2,3dithiobutyl-4-thianaphthenyl)-N-p-chlorohexyl urea is added. At the endoffifteen minutes reflux time all except a very small amount of materialdissolves. The flask is cooled in an ice bath and the small amount ofinsoluble material, along with an additional quantity of material whichseparates on cooling, is removed by filtration. (30 ml.) is added slowlyand a precipitate forms. The precipitate is extracted with three 250 ml.portions of chloroform and the combined extracts washed with water. Theorganic layer is dried over anhydrous sodium sulfate and concentrated invacuo. The crystalline residue which forms is triturated with ether anddried.

The compound 2-(2,3-dithiobutyl-Z-thianaphthenyl amino)-oxazoline wassimilarly prepared from N'-(2,3- dithiobutyl 2thianaphthenylamino)-N'-t8-bromoethyl urea.

EXAMPLE XIII- N -(4,5,6-tribut0xy-7-benzofuranyl)-N'-a,fi-dimethyllit-chloroethyl urea EXAMPLE XIV2-(4,5,6-tribut0xy-7-benzofuranylam'ino)4,5 dimethyloxazoline One literof water is brought to boiling and 15 g. of N (4,5,6tributoxy-7-benzofuranyl)-N-a,fi-dimethyl-flchloroethyl urea is added.At the end of fifteen minutes reflux time all except a very small amountof material dissolves. The flask is cooled in an ice bath and the smallamount of insoluble material, along with an additional quantity ofmaterial which separates on cooling, isremoved by filtration. A 14%solution of ammonium hydroxide (30 ml.) is added slowly and aprecipitate forms. The precipitate isextracted with three 250 ml.portions of chloroformand. the combined extracts washed with water. Theorganic layer is dried over anhydrous sodium sulfate and concentrated invacuo. The crystal- A 14% solution of ammonium hydroxide EXAMPLE XV N-(2,4-a'ibutyl-3-thianaphthenyl) -N'-fi-(p-t0luenesulfonyloxy) ethyl ureaA solution of ice cold 50% potassium hydroxide (150 g.) is shaken with asuspension of 100 g. of 2,4- dibutyl-3-thianaphthenylamine hydrobromidein 420.ml. of benzene. The benzene layer containing the free base isseparated and dried over a small amount of potassium hydroxide. Thedrying agent is removed by filtration. To this solution an equimolarbenzene solution of B- (p-toluenesulfonyloxy) ethyl isocyanate is addeddroywise with cooling. The solution is allowed to stand for one hourduring which time the product separates and is recovered by filtration.

EXAMPLE XVI 2-(2,4-dibutyl-3-thianaphthenylamino)-0xaz0line One liter ofwater is brought to boiling and 15 g. of N (2,4 dibutyl-3thianaphthenyl)-N'- -(p-toluenesulfonyloxy) ethyl urea is added. At theend of fifteen minutes reflux time all except a very small amount ofmaterial dissolves. The flask is cooled in an ice bath and the smallamount of insoluble material, along with an additional quantity ofmaterial which separates on cooling, is removed by filtration. A 14%solution of ammonium hydroxide (30 ml.) is added slowly and aprecipitate forms. The precipitate is extracted with three 250 ml.portions of chloroform and the combined extracts washed with water. Theorganic layer is dried over anhydrous sodium sulfate and concentrated invacuo. The crystalline residue which forms is triturated with ether anddried.

The compound 2-(2,4-dibutyl-4-thianaphthenylamino)- oxazoline wassimilarly prepared from N-(2,4-dibutyl-4-thianaphthenyl)-N'-{3-bromoethyl urea.

EXAMLE XVII N 3,4,5 -trichlr0-6-benz0 furanyl N '-fi-chl0r0ethyl urea Asolution of ice cold 50% potassium hydroxide (150 g.) is shaken with asuspension of 120 g. of ti-chloroethylamine hydrochloride in 420 ml. ofbenzene. The benzene layer containing the free base is separated anddried over a small amount of potassium hydroxide. The drying agent isremoved by filtration. To this solution an equimolar benzene solution of3,4,5-trichloro-6-benzofuranyl isocyanate is added dropwise withcooling. The solution is allowed to stand for one hour during which timethe product separates and is recovered by filtration.

EXAMPLE XVIII 2-(3,4,5-trichl0ro-6-benzofuranylamino)-0xaz0line Oneliter of water is brought to boiling and g. of

(3 ,4,5-trichloro-6-benzofuranyl -N'-B-chloroethyl urea is added. At theend of fifteen minutes reflux time all except a very small amount ofmaterial dissolves. The flask is cooled in an ice bath and the smallamount of insoluble material, along with an additional quantity ofmaterial which separates on cooling, is removed by filtration. A 14%solution of ammonium hydroxide ml.) is added slowly and a precipitateforms. The precipitate is extracted with three 250 ml. portions ofchloroform and the combined extracts washed with water. The organiclayer is dried over anhydrous sodium sulfate and concentrated in vacuo.The crystalline residue which forms is triturated with ether and dried.

The compound 2-(3,4,5-trichloro-7-benzofuranylamino)-oxazoline wassimilarly prepared from N-(3,4,5-trichloro-7-benzofuranyl) -N8-brornoethyl urea.

10 EXAMPLE XIX N- (2-bromo-3- iodo-4-thianaphzhenyl)-N'-fi= bromoethylarea A solution of ice cold 50% 7 potassium hydroxide g) is shaken withasuspension of 123 g. of fibI'OmOC thYI- amine hydrobromide in 420 ml. ofbenzene. The benzene layer containing the free base is separated anddried over a small amount of poatssium hydroxide. The drying agent isremoved by filtration. To this solution an equimolar benzene solution of2-bromo-3-iodo-4-thianaphthenyl isocyanate is added dropwise withcooling. The solution is. allowed to stand for one hour during whichtime the product separates and is recovered by filtration.

EXAMPLE XX V 2-(Z-brom0-3-i0d0-4-thianaphthenylamino)-0xaz0line Oneliterof water is brought to boiling and 15 g. of

-(2-bromo-3-iod0-4thianaphthenyl)-N'-fi bromoethyl urea is'added. At theend of fifteen minutes reflux time all except a very small amount ofmaterial dissolves. The flask is cooled in an' ice bath and the smallamount of insoluble material, along with an additional quantity ofmaterialwhich separates on cooling, is removed by filtration. A 14%solution of ammonium hydroxide (30 ml.) is added slowly and aprecipitate forms. The precipitate is extracted with three 250 ml.portions of chloroform and the combined extracts washed with water. Theorganic layer is dried over anhydrous sodium sulfate and concentrated invacuo. The crystalline residue which forms is triturated with ether anddried.

The compound 2-(2-bromo-3-iodo 4 benzofuranylamino)-oxazoline wassimilarly prepared from N'-(2- bromo-3-iodo-4-benzofuranyl)-N'-3-bromoethyl urea.

EXAMPLE 2-(5,6-dibromo-3-thianaphthenylamino)-0xaz0line sulfate A 15%aqueous solution of 2-(5,6-dibromo-3-thianaphthenylamin-o) -oxazolinehydrochloride is stirred for three hours with an anion exchange resinwhich had been previously washed with aqueous sulfuric acid. The resinwas removed by filtration and the solvent removed in vacuo to leave asulfuric acid addition salt as a residue.

Included among the anion exchange resin used for this process wereAmberlite IRA-410 and Amberlite IRA-400 available from Rohm & HaasCompany, as well as Dowex-l and Dowex-Z available from the Dow ChemicalCompany.

A number of other acid addition salts are prepared using this procedureand these include the acetate, citrate, valerate, gluconate, nitrate,tartrate and phosphate.

EXAMPLE XXII A tablet base is prepared by blending the following in-'gredients in the proportion by weight indicated.

Into this tablet there is blended a suificient amount of 2-(3-methyl-2-benzofuranylamino)-oxazoline to provide tablets eachcontaining 25 mg. of active ingredient.

EXAMPLE XXIII Into the tablet base of Example XXII there is blended asufficient amount of N-(2iodo-3-thianaphthenyl)-N'-' fl-bromoethyl ureato provide tablets each containing 0.5 mg. of active ingredient.

A tablet base is prepared by blending. the following ingredients in theproportion by weight indicated.

Grams Sucrose, U. S-. P 80.3 Tapioca star 13.2 Magnesium stearate 6.5

Into this base there is blended a sufficient amount of N-(2,3-diethoxy-4-benzofuranylamino)-oxazoline to provide tablets eachcontaining. 50 mg. of active ingredient.

EXAMPLE XXV Into the tablet base of Example XXIV there is blended asufficient amount of N-(2,3-dibromo-5-thianaphthenylamino)-oxazoline toprovide tablets each containing 1 mg. of active ingredient.

EXAMPLE XXVI An aqueous solution containing 0.005% by weight of N-(3-ethyl-2-benzofuranylamino) oxazoline hydrochloride. is prepared bydissolving the salt in U. S. P. distilled water.

EXAMPLE XXVII 'What is claimed is:

1. A compound selected from the group consisting of substituted andunsubstituted 2 (benzofuranylamino)- oxazolines,Z-(thianaphthenylamino)-oxazolines and their pharmaceutically acceptableacid addition salts wherein; (a) each substituent on a substitutedbenzofuranyl and thianaphthenyl ring is selected from the groupconsisting of alkyl, alkoxy and thioalkyl groups each containing up tofour carbon atoms, and chlorine, bromine and iodine atoms, there beingfrom one to three such substituents, and (b) each substituent on asubstituted methylene group of the oxazoline ring is selected from thegroup consisting of one to four carbon atom alkyl groups, there being atotal of from one to eight carbon atoms in such substituents.

2. 2-(Z-benzofuranylamino)-oxazoline.

3. 2-(Z-thianziphthenylamino)-oxazoline.

4. 2-( 3,4-dimethyl-5-benzofuranylamino) -5-ethyloxa'- zoline.

5. 2-(2,3-dithiobutyl-4-thianaphthenylamino)-5 butyloxazoline.

6. 2-(2,4-dibutyl-3-thianaphthenylamino)-oxazoline.

References Cited in the file of this patent UNITED STATES PATENTS2,027,031 Engelmann I an. 7, 1936 2,450,807 McCarthy Oct. 5, i9482,517,826 Avakian et al Aug. 8, 1950 2,548,704 Coleman et a1 Apr. 10,1951 2,727,042 Jacob Dec. 13, 1955 2 ,811,529 Bloom Oct. 29, 1957'

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF SUBSTITUTED AND UNSUBSITUTED 2 - (BENZOFURANYLAMINO)OXAZOLINES, 2-(THIANAPHTHENYLAMINO)-OXAZOLINES AND THEIR PHARMACEUTICALLY ACCEPTABLE ACID ADDITION SALTS WHEREIN; (A) EACH SUBSTITUENT ON A BENZOFURANYL AND THIANAPHTHENYL RING IS SELECTED FROM THE GROUP CONSISTING OF ALKYL, ALKOXY AND THIOALKY GROUPS EACH CONTAINING UP TO FOUR CARBON ATOMS, AND CHLORINE, BROMINE AND IODINE ATOMS, THERE BEING FROM ONE TO THREE SUCH SUBSTITUENTS, AND (B) EACH SUBSTITUENT ON A SUBSTITUTED METHYLENE GROUP OF THE OXAZOLINE RING IS SELECTED FROM THE GROUP CONSISTING OF ONE TO FOUR CARBON ATOM ALKYL GROUPS, THERE BEING A TOTAL OF FROM ONE TO EIGHT CARBON ATOMS IN SUCH SUBSTITUENTS. 